Background: In the past decade, several therapies have been approved for patients (pts) with mCRPC, including the androgen receptor (AR) antagonist enzalutamide (enza) and the androgen synthesis inhibitor abiraterone acetate (abi). Despite these advances, most pts experience disease progression and there are inadequate data to guide the sequencing of agents to optimize outcomes. Pts with mCRPC who progress on enza have increased circulating PD-L1/PD-L2–positive dendritic cells compared with enza-naive pts or pts who are still responding to treatment (Bishop et al. Oncotarget. 2014). In two recent studies, PSA and radiographic responses were observed in mCRPC pts treated with a PD-L1/PD-1 pathway inhibitor with or without enza (Graff et al. Oncotarget. 2016; Hansen et al. Ann Oncol. 2016). Atezolizumab (atezo) is an anti–PD-L1 monoclonal antibody that inhibits the interaction between PD-L1 and its receptors, PD-1 and B7.1, enhancing T-cell responses and improving anti-tumor activity. Taken together, this suggests that the combination of atezo and enza may provide an effective treatment option for mCRPC pts. Methods: A Phase III randomized, multicenter, clinical trial (NCT03016312) is being conducted to evaluate the efficacy and safety of atezo with enza compared with enza alone in mCRPC pts who have received prior abi treatment and have progressed on, are ineligible for, or have refused a taxane regimen. Eligibility criteria include mCRPC or locally advanced, incurable CRPC and ECOG PS 0-1. Exclusion criteria include CNS metastasis, autoimmune disease, history of seizures, prior immunotherapy and prior treatment with enza or any other newer AR antagonists. Pts will be randomized 1:1 to receive atezo 1200 mg q3w and enza 160 mg qd or enza alone. The primary endpoint is OS, and secondary endpoints include PSA response rate, rPFS, ORR and safety. Exploratory biomarkers associated with responses to atezo and enza will be evaluated in tumor tissue collected at baseline and progression. Approximately 550 pts will be enrolled at 150 sites globally. Clinical trial information: NCT03016312